Alzheimer's disease (AD) is the most common neurodegenerative disorder in humans. The disease is characterized by a progressive impairment in cognition and memory. The hallmark of AD at the neuropathological level is the extracellular accumulation of the amyloid-β peptide (Aβ) in “senile” plaques, and the intracellular deposition of neurofibrillary tangles made of the microtubule-associated protein Tau. In neuronal tissue of AD patients, Tau is hyperphosphorylated and adopts pathological conformations evident with conformation-dependent antibodies. The amyloid-β peptide is a cleavage product of the amyloid precursor protein (APP). In normal individuals, most of Aβ is in a 40-amino acid form, but there are also minor amounts of Aβ that are 42 amino acids in length (Aβ42). In patients with AD, there is an overabundance of Aβ42 that is thought to be the main toxic Aβ form.
A number of transgenic mouse models have been generated that express wild-type or mutant human APP. The mutant form of APP is differentially cleaved to result in increased amounts of Aβ42 deposited within Aβ plaques. These transgenic mice present with neurological symptoms of Alzheimer's disease, such as impaired memory and motor function (Janus C. et al., Curr. Neurol. Neurosci. Rep 1 (5): 451-457 (2001)). A transgenic mouse that expresses both mutant human APP and mutant human Tau has also been generated (Jada, et. al., Science, (5534) 293:1487-1491 (2001)). This double transgenic mouse is a rodent model for AD that shows enhanced neurofibrillary degeneration indicating that either APP or Aβ influences the formation of neurofibrillary tangles.
Mouse models have proven very useful for testing potential AD therapeutics. However, the use of mice for testing therapeutics is both expensive and time consuming. Thus, it would be beneficial to find alternative models which are less expensive and that can be efficiently used to screen for therapeutic agents for Alzheimer's disease. For example, non-mammalian animal models, such as Caenorhabditis elegans or Drosophila melanogaster. 
Although human amyloid precursor protein (APP) has been expressed in Drosophila melanogaster (Fossgreen, et. al., PNAS 95:13703-13708 (1998); Yagi et al., Mol. Cell. Biol. Res. Comm. 4: 43-49 (2000)), the expression of human APP in Drosophila has proven unsuccessful for generating disease models with Aβ42 plaque depositions. Cohen et. al. (U.S. Pat. Appl. Pat. No. 2002/0174446) discloses a transgenic Drosophila carrying a cDNA encoding Aβ42 peptide fused to a signal peptide. Expression of Aβ42 in the Drosophila eye of this model reportedly exhibits a rough-eye phenotype. However, expression levels of Aβ42 peptide are variable, and only high levels of Aβ42 peptide results in the rough-eye phenotype of the fly. Transgenic Drosophila over-expressing wild-type and mutant forms of human Tau also have been generated (Wittman et al., Science 293:711-714 (2001); Jackson et al., Neuron 34: 509-519 (2002)). In flies, expression of human Tau can lead to shortened life-span, loss of cholinergic neurons (Wittman et al., Science 293:711-714 (2001)) and eye phenotypes (Jackson et al., Neuron 34: 309-519 (2002)). However, these wild type and mutant transgenic Tau fly models do not develop, on their own, neurofibrillary tangles characteristic of human AD. Neurofibrillary pathology was only observed when combined with other alterations in genes of the Wint signaling pathway (Jackson et al., Neuron 34: 309-519 (2002)).
Thus, despite significant advances in the field, there is still a need in the art for improved non-mammalian animal models of Alzheimer's disease that can be easily and inexpensively generated for screening potential therapeutic agents.